Clinical Significance of Heterozygosity for Mutations of the SLC12A3 Gene Coding for the Thiazide Sensitive Na-Cl Cotransporter

Heterozygous Carriers of Gitelman Syndrome Clinical Trial

— HEPHYGI  

Official title:

Clinical Significance of Heterozygosity for Mutations of the SLC12A3 Gene Coding for the Thiazide Sensitive Na-Cl Cotransporter

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02035046
• Other study ID #: P120111
• Status: Completed
• Phase: N/A
• First received: December 18, 2013
• Last updated: January 13, 2017
• Start date: December 2013
• Est. completion date: September 2016

Study information

• Verified date: January 2017
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Gitelman syndrome is a salt wasting tubulopathy caused by mutations in the SLC12A3 gene coding for the thiazide sensitive sodium chloride cotransporter. This disease mimics the chronic treatment with thiazide diuretics and is characterized by renal hypokalemia, low to normal blood pressure, hypocalciuria and hypomagnesemia. The purpose of this study is to determine whether the heterozygous carriers present the metabolic risks and/or the benefits of this disease.

Description:

Gitelman syndrome (GS), is an autosomal recessive salt wasting tubulopathy caused mainly by loss of function mutations in the SLC12A3 gene coding for the thiazide sensitive sodium-chloride cotransporter (NCC). Thus, GS mimics a chronic treatment with high doses of thiazide diuretics. NCC is expressed in the distal convoluted tubule, which is responsible for 7% of NaCl reabsorption. GS is the more frequent hereditary tubulopathie with estimated prevalence of 1/40000, which implicates that 1% of general population are heterozygous carriers (600 000 in France). Previous publications suggest that the apparently asymptomatic heterozygous carriers could present some clinical traits of GS or chronic thiazide treatment. These including: beneficial aspects (low blood pressure, low urinary calcium excretions) or metabolic risks (hypokalemia, insulin resistance). Nevertheless, these studies do not evaluate all the aspects and blood pressure was evaluated once in hospital setting. This study aims to compare home monitoring blood pressure; salt balance; potassium, glucose lipid and mineral metabolism and vascular function in 80 heterozygous carriers, 80 GS patients and 80 controls persons (without mutations in SLC12A3 gene).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 250
• Est. completion date: September 2016
• Est. primary completion date: September 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Gitelman syndrome patients, relatives carrying heterozygous mutations and relatives or healthy voluntarees without mutations.

Related Conditions & MeSH terms

• Gitelman Syndrome
• Heterozygous Carriers of Gitelman Syndrome

Intervention

Procedure:
• Samplings of blood

• Sampling of urine

• Measure of the blood pressure

• glycemia test

Locations

Country	Name	City	State
France	Nephrology Department. Centre Hospitalier Universitaire, Hôpital Dupuytren	Limoges
France	Department of Functional Investigations. Hospices Civils de Lyon, Hôpital Edouard Herriot.	Lyon
France	Clinical Research Center. Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou.	Paris
France	Department of Functional Investigations. Assistance Publique Hôpitaux de Paris, Hôpital Tenon	Paris
France	Department of Functional Investigations. Centre Hospitalier Universitaire, Hôpital de Rangueil.	Toulouse

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Ministry of Health, France

Country where clinical trial is conducted

France, 

References & Publications (6)

Cruz DN, Simon DB, Nelson-Williams C, Farhi A, Finberg K, Burleson L, Gill JR, Lifton RP. Mutations in the Na-Cl cotransporter reduce blood pressure in humans. Hypertension. 2001 Jun;37(6):1458-64. — View Citation

Fava C, Montagnana M, Rosberg L, Burri P, Almgren P, Jönsson A, Wanby P, Lippi G, Minuz P, Hulthèn LU, Aurell M, Melander O. Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure. Hum Mol Genet. 2008 Feb 1;17(3):413-8. — View Citation

Hsu YJ, Yang SS, Chu NF, Sytwu HK, Cheng CJ, Lin SH. Heterozygous mutations of the sodium chloride cotransporter in Chinese children: prevalence and association with blood pressure. Nephrol Dial Transplant. 2009 Apr;24(4):1170-5. doi: 10.1093/ndt/gfn619. — View Citation

Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008 May;40(5):592-9. doi: 10.1038/ng.118. — View Citation

Ren H, Qin L, Wang W, Ma J, Zhang W, Shen PY, Shi H, Li X, Chen N. Abnormal glucose metabolism and insulin sensitivity in Chinese patients with Gitelman syndrome. Am J Nephrol. 2013;37(2):152-7. doi: 10.1159/000346708. — View Citation

Tago N, Kokubo Y, Inamoto N, Naraba H, Tomoike H, Iwai N. A high prevalence of Gitelman's syndrome mutations in Japanese. Hypertens Res. 2004 May;27(5):327-31. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Systolic blood pressure evaluated by self-measurement	self-measurement at home, 3 times a day during 3 consecutive days	3 days
Secondary	Salt balance	Blood renin and aldosterone measurements, 24h urinary sodium and aldosterone excretion	1 day
Secondary	Potassium metabolism	Dietary intake, blood potassium and 24 h urinary potassium excretion	1 day
Secondary	Glucose and lipide metabolism	BMI, blood glucose, insulin, cholesterol, LDL, HDL and triglycerides.	1 day
Secondary	Oral glucose tolerance test		1 day
Secondary	Mineral metabolism	Blood and urinary calcium, magnesium and phosphate. bone remodeling markers	1 day
Secondary	Renal fonction	Estimated GFR, proteinuria and albuminuria	1 day
Secondary	Vascular fonction evaluation	Pulse wave analysis and central blood pressure. Blood and urinary vascular fonction markers	1 day